The objectives of this proposal are to study in experimental animals and in man the mechanisms involved in: initiation (causes) of seizures, by convulsant drugs to produce generalized seizures and metal implantation of cobalt or ferric chloride to produce focal seizures; arrest of seizures, by intrinsic mechanisms involving recruitment of inhibitory systems, enhancing glial transport systems that maintain homeostasis in the interstitial fluid environment of the neurons, and by anticonvulsant drugs (treatment); and prevention of sezures, by augmenting the intrinsic glial regulatory mechanisms at the time insults to the brain are received. Particularly to be emphasized are studies on the pharmacokinetics and mechanisms of action of convulsant and anticonvulsant drugs. Also to be studied are the factors that affect susceptibility to seizures. A multifacted approach will be used that involves measurement of active transport processes, transport enzymes, neurotransmitters, protein and nucleic acid synthesis, CO2-fixation and neuropharmacological assessment of the animals. The effects of anticonvulsants and convulsants on maturation and aging will also be assessed. Development of new experimental models of epilepsy, including biochemical and maturational studies of audiogenic seizures in mice, based on mechanisms of action of the convulsants rather than on seizure type will also be done. Some potentially new anticonvulsants will also be studied by these approaches. Appropriate clinical studies will be done on mentally retarded children on the pharmacokinetics, efficacy, interactions, and toxicity of various antiepileptics alone and in combination with valproate Na to correlate the basic data on animals with that obtained in man.